Certain monoamides of hydantoic acid



4 2,928,973 CERTAIN MONOAMIDES F HYDANTOIC ACID 2,928,873 Patented Mar. 15, 1960 methylamine. After standing at 20 C. for 16 days, the

product, the substituted hydantoamide of the'following formula Seymour LlShapii-o, Hastings on Hudson, and Louis 5 H H Freedman,-Bronxville, N.Y.,-assignors to US. Vitamin I Y I l and Pharmaceutical Corporation, New York, N.Y., a fiT f fi corporation of Delaware o- H? No Drawing l Application January 7, 1959 Serial No. 785,330

6 Claims (CL 269 553) was separated in a yield of 8.7 g. (77%) and on recrystallization (water), melted at 209-211" C. In a similar manner and using variants of RCH NH gs mventwn concerned t N-substltuted hy anthe corresponding hydantoamides characterized in Table toamides and particularly with hydantoamides of the fol- I were prepared. lowin formula g Table I H I HYDANTOAMIDES NHr-CNCH2CNCH2R H II I ROH N-C-CH N-CNH wherein R is an alkyl, cycloalkyl, aryl, and arylalkyl rrgroup having a carbon content of C -C Analyses, Percent M.P., No. R 0. Formula Carbon Hydrogen Nitrogen Caled. Found Calcd. Found Calcd. Found 1..-. (embolism-n" 201-202 oaflnNlot. 51.3 51.4 9.2 9.3 22.4 22.3 2. CH3(CH2)s CaHnNsOn. 51.3 50.9 9.2 9.1 22.4 22.5 3-.-- CHa(CH2)5 Ciel-121N30 55.8 56.3 i 9.8 9.7 19.5 19.2 4-- C H CIIHNNSOL 58.6 58.3 8.5 8.1 5.--- C4Ha0- CsHnNzQs 48.7 48.8 5.6 5.7 21.3 20.6 6 phenyl.- CmHrsNzO: 58.0 58.2 6.3 6.7 20.3 20.0 7..-- pchloroph 01011120119301-.- 49.7 50.0 5.0 5.4 17.4 17.4 s. benzyl CUHMNBO: 59.7 00.0 6.8 6.6 19.0 18.6 9.--- CafInNsOa 10 HOOHL-.. CsHuNaOa 37.3 37.3 6.9 6.6 26.1 26.0 CHFOH- CUHHNSOH 45.9 45.9 7.1 7.1 26.7 26.8

=2,5-endomethylenecycl0hexyl. =2-furyl.

The compounds within the structural ambit of this invention show potent anti-inflammatory activity when evaluated by standard procedures.

The compounds of the invention are stable, white, somewhat water-soluble, crystalline solids which are conveniently prepared by the reaction of the. appropriate amine RNH, with ethyl hydantoate in a lower alcohol.

The invention will be more fully described from the examples which follow. These examples are set forth by way of illustration only, and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, since many modifications in materials and methods will be apparent from this disclosure to those skilled in the art.

EXAMPLE 1 The compounds within the ambit of this invention show high anti-inflammatory responses, for example, with a lethal dose minimum in mice subcutaneous (LD there is obtained an anti-inflammatory efiect in units per gram (outline of procedure given in Shapiro et al., J. Am. Pharm. Assoc., Sci. Ed., 46, 333 (1957)): compound 2 (DL over 1000 mg./kg.) has an activity of 7.5 units per gram; compound 4 (LD of 200 mg./kg.) shows activity of 10 units per gram; and compound 6 (LD,,,,,, of 100 mg./kg.) has an anti-inflammatory activity of units per gram. For purposes of comparison, sodium salicylate has an LD of 400 mg./kg. and an anti-inflammatory activity of 2 units per gram.

In contrast to the compounds of this invention, the compounds made for purposes of comparison (compounds 9-11) show activity of no greater than 2 units per gram in any instance, and compound 9 shows no activity whatever.

The novel compounds of this invention can be combined with solid or liquid pharmaceutical carriers and formulated into the form of tablets, powder packets or capsules, or dissolved in suitable solvents for oral and parenteral administration for human or veterinary use.

3 'It is to be understood that it is intendeci to cover all changes and modifications of the examples herein chosen for the purpose of illustration which do not constitute departures from the spirit and scope of the invention.

, We claim:

L'Th c compound wherein R is a rhember of the group consisting of hydrocarbon alkyl, said alkyl having a carbon content C -C hydrocarbon cycloalkyl, said cycloalkyl having a carbon content C -C phenyl, pchiorophenyl, -Z-furyi,

and"benzy1. a 1 2. The compound of clairn 1 wherein R is phenyl. 3. The compound of claim 1 wherein R is CH CH CH CHr T e ompo n of l i 1 h rein 1.1 is. (Li-en domethyiene)cyclohexyl-.

5. The compound of claim 1 whereintkisjbenzyl.

6. The compound-of ciaim '1" wherein-R in Noreferences cited 

1. THE COMPOUND
 2. THE COMPOUND OF CLAIM 1 WHEREIN R IS PHENYL. 